Increase In Plasma Immunoreactive Insulin Research Articles

Hypoglycemic effects of Salvadora persica L. in the rat

The stem decoction of Salvadora persica L., a drug widely used as a tooth cleaning stick in Arabian countries, shows, in normal rats, hypoglycemic effects, an increase in plasma immunoreactive insulin (IRI) and an incremented oral-glucose tolerance. The decoction also causes a significant decrease in mean body weight without drastic reduction in food consumption.

Hypoxia-Induced Sympathetic Inhibition of the Fetal Plasma Insulin Response to Hyperglycemia

Large-for-delivery date babies, considered characteristic of diabetic pregnancy, are believed to result from fetal hyperinsulinemia. Paradoxically, infant birth weights tend to be low-for-delivery date in mothers with more severe diabetes. We tested the hypothesis that hypoxemia in such fetuses leads to sympathoadrenal stimulation and inhibition of insulin secretion; and, thus, produces a net reduction in the growth-promoting effects. Fetal sheep were prepared with chronic peripheral and adrenal cannulas. Fetal blood gases, lactate, norepinephrine, and epinephrine secretion rates; and plasma norepinephrine, glucose, and immunoreactive insulin concentrations were determined at 30-min intervals during a 2-h baseline period and a 4-h period of hyperglycemia divided into 2-h segments of hypoxemia (with and without alpha-blockade) and hyperoxia. Hypoxemia-hyperoxia sequences were varied randomly. Well-oxygenated fetuses responded to a threefold increase in glucose with a sixfold increase in plasma immunoreactive insulin. With hypoxemia, norepinephrine and epinephrine secretion were elevated and the insulin response was blocked. With hypoxemia and phentolamine blockade, the insulin response was enhanced with a 10-fold increase above baseline. In severe maternal diabetes with vascular disease or with poor control and very high glucose levels, the fetus is likely to be relatively hypoxemic. Our experiments suggest that in this situation, the fetal insulin response to hyperglycemia will be attenuated; this effect is mediated, at least partly, through sympathoadrenal stimulation.

Pancreatic polypeptide response to oral glucose load in patients with liver cirrhosis--interrelationship between PP and other pancreatic endocrine hormones

The purpose of the present study was to elucidate the interrelationship between pancreatic polypeptide (PP) and other pancreatic endocrine hormones. For this purpose, a radioimmunoassay (RIA) system of plasma PP was established and the changes in plasma PP, plasma immunoreactive insulin (IRI), plasma C-peptide reactivity (CPR) and plasma immunoreactive glucagon (IRG) following oral administration of glucose were examined in ten normal subjects and twenty-five patients with liver cirrhosis. Patients with liver cirrhosis were classified into a normal glucose tolerance group (NGT), an impaired glucose tolerance group (IGT), and a diabetes mellitus group (DM) on the basis of the glucose tolerance curves obtained after the oral administration of glucose. In the IGT and DM groups, fasting plasma PP levels were significantly elevated when compared with those in the control and NGT groups. Also oral administration of 75g glucose elicited an exaggerated rise in plasma PP in the IGT and DM groups when compared with the response in the control and NGT groups. On the other hand, PP response to glucose in the NGT group was similar to that in the control group. Plasma IRI increased markedly before and after oral administration of glucose in the IGT and DM groups when compared with the control groups. In these patients, plasma levels of CPR almost paralleled those of IRI. No significant difference was noted between the NGT group and the control group with regard to plasma IRI and CPR levels before and after oral glucose loading. Accordingly, insufficient insulin action was considered to exist in the IGT and DM groups. This insufficiency in insulin action was expressed in terms of the indices of increase in plasma IRI and CPR, delta IRI/delta BS and delta CPR/delta BS, which corresponded to the elevated blood glucose levels, being significantly lower in the IGT and DM groups than in the control and NGT groups 30 minutes after oral administration of glucose. No significant difference was noticeable between the NGT group and control group with regard to these indices. In the patients with liver cirrhosis, the delta PP value, obtained by subtracting the plasma PP level during fasting from the PP level 30 minutes after oral glucose loading, was inversely correlated with the values of both delta IRI/delta BS and delta CPR/delta BS.(ABSTRACT TRUNCATED AT 400 WORDS)

Degranulation effect of ferric nitrilotriacetate (Fe3+-NTA) on the pancreatic islet beta-cells: its acute toxic effect on glucose metabolism.

A single injection of ferric nitrilotriacetate (Fe3+-NTA) caused a transitory increase in plasma immunoreactive insulin (IRI) and plasma immunoreactive glucagon (IRG) in rats. They reached maximum levels at 2 days after injection and returned to the normal range at 10 days. At 2 days after Fe3+-NTA injection, blood glucose level was normal but the glucose tolerance test (GTT) was impaired. There was a further increase in plasma IRI level and IRG level was suppressed after glucose loading. At 10 days after Fe3+-NTA injection, glucose tolerance was normal and IRI also returned to the normal range. No degenerative changes were found on H.E.-stained rat pancreatic tissue sections after Fe3+-NTA injection. Histochemical staining, however, showed a reduction in beta-granules and heavy metals (Timm's granules) from islet cells in the central area of the rat pancreatic islet 1 to 3 days after injection of Fe3+-NTA. The fading remained in some islets even at 10 days after injection, but by then the beta-granule distribution was restored in most islet cells. The results indicate a single Fe3+-NTA injection induced transitory instability of the pancreatic islet beta-cell granules and the glucose intolerance with a hyperresponse of IRI.

Hypoglycemic activity of l-α-(3,4- dimethoxyphenethylaminomethyl)-2- hydroxybenzylalcohol [formula omitted] fumarate (TA-078) in the mouse, rat and dog

l-α-(3,4-Dimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol 1 2 fumarate (TA-078) is a new hypoglycemic agent structurally different from any existing hypoglycemic drug. It depresses the rise of blood glucose when it is orally administered to glucose-loaded mice, rats and beagle dogs at minimal doses of 1, 10 and 2.5 mg/kg, respectively. In contrast with tolbutamide, TA-078 hardly affected fasting blood glucose levels in rats and dogs and only weakly reduced fasting blood glucose levels in mice. Oral administration of TA-078 to KK mice also improved glucose tolerance, while no improvement was observed in streptozotocin-diabetic rats. TA-078 elevated plasma immunoreactive insulin (IRI) levels in mice and rats soon after its oral administration. In fasted rats, TA-078 caused only a transient increase in plasma IRI but did not affect plasma immunoreactive glucagon (IRG) levels in the early phase after its administration. On the other hand, tolbutamide induced a sustained increase in plasma IRI and a transient but marked decrease in plasma IRG. In perfused rat pancreas, TA-078 stimulated insulin secretion. The stimulation by 10 μg/ml TA-078 in the perfusion liquid required the presence of a normal concn (5.6 mM) of glucose, whereas the same concn of tolbutamide stimulated insulin release even at a low glucose concn (2.8 mM).

Hypothalamic obesity induced by monosodium glutamate (MSG) in rats: changes in the endocrine pancreas in the course of and after induction obesity

It has been reported that the neonatal administration of monosodium glutamate (MSG) in rodents produces lesions of the arcuate nucleus and the ventromedial nucleus of the hypothalamus and results in obesity in adulthood. Though there are a large number of reports using MSG-treated animals, most of them deal with neuronal and neuroendocrinological pathophysiology within the central nervous system. The present study, therefore, was designed to investigate the time-course of metabolic and hormonal changes in relation to the development of hypothalamic obesity induced by MSG in female Wister rats. In addition, responses of insulin and somatostatin to glucose loading were examined in rats with hypothalamic obesity. MSG, 2mg per g of body weight, was subcutaneously injected for 5 consecutive days after birth. Body weight, plasma glucose and immunoreactive insulin (IRI) were measured at one- to four-week intervals in rats aged from 6 days to 11 months. The Lee index, plasma triglyceride and immunoreactive glucagon (IRG) were measured at one-month intervals from one to 11 months. Immunoreactive somatostatin (IRS) and gastrin (IRGa) were determined at the 7th month or later. All parameters in plasma described above were assayed on samples drawn from the jugular vein. In addition, IRI and IRS in the pancreas were measured until 6 months. Further, responses of glucose, IRI and IRS to intragastric glucose loading (3g/kg body weight) were examined in portal plasma at the 11th month. All parameters in the MSG rats were compared with those in age-matched female controls which received the vehicle alone. Plasma IRI was elevated by 54% in the MSG rats even at the 6th day. Thereafter, the MSG rats showed a progressive increase in plasma IRI which was 96% and 237% higher at the 1st and 3rd month, respectively. Parallel with the change in plasma IRI, there was a constant 1.5-fold elevation of pancreatic IRI in the MSG rats aged between the 21st day and the 6th month, though pancreatic IRI decreased by 20% at 6 days. Pancreatic IRS also increased at the 21st day, but thereafter decreased by 48% at the 6th month. A progressive increase in plasma TG which was 37,139,203 and 279% higher at 2, 3, 4 and 5 months, respectively, was followed by a 2- to 3-fold elevation during following 6 months. The MSG rats showed a constant 20% reduction in body weight for the first 2 months, but thereafter showed a progressive increase throughout the observation which was 17, 39 and 55% higher at 4, 7 and 11 months, respectively. The Lee index of obesity also progressively increased from 337 ± 4 at the 3rd month to 390 ± 6 at the 8th month, but thereafter maintained a constant 1.2-fold elevation. In contrast with the marked changes in plasma IRI, no significant differences in plasma glucose were found between the two groups for the entire period of observation. Plasma IRG also showed a constant 1.2- to 2.0-fold elevation irrespective of the duration of obesity. Rats with obesity induced by MSG had markedly elevated levels of IRI and IRS not only in jugular plasma but also in portal plasma. In addition, responses of the two hormones to intragastric glucose loading were exaggerated in portal plasma, whereas response of plasma glucose was unchanged. Plasma IRGa was also observed to be increased by 38 - 81%. These findings indicate that hyperinsulinemia is the primary factor in the development of hypothalamic obesity induced by MSG. Hypothalamic obesity induced by neonatal administration of MSG in the rat is characterized by hypersecretion of glucagon and somatostatin as well as insulin, and may provide a readily available and valuable animal model for studying the hypothalamico-pancreatic axis.

Glucose-Lowering Effect of Insulin by Different Routes in Obese and Lean Nonketotic Diabetic Patients*

The absorption of insulin and its glucose-lowering effect were compared after the administration of crystalline insulin by sc, im, and iv routes in 29 obese and 10 lean nonketotic diabetic patients, none of whom had consciously received insulin previously. Each of the patients received insulin in a dose of 0.1 U/kg BW by the im, sc, and iv routes in a randomized fashion on 3 different days. Plasma glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) were measured at intervals over the first 4 h. The t1/2 (mean +/- SEM) after iv administration of insulin in obese and lean diabetics was, respectively, 5.3 +/- 0.2 and 4.8 +/- 0.4 min; these were not significantly different. Intravenous injection produced its highest level of IRI in 2 min in both groups. Thereafter, a rapid drop was observed with return to the basal level by 90 min. Equivalent amounts of im and sc insulin produced a maximal increase in plasma IRI at 60 min in both groups. Plasma IRI after iv insulin injection was significantly higher than after sc and im insulin injections at 10 and 20 min (P less than 0.001) and significantly lower than the im and sc groups at 60, 90, 120, 150, 180, 210, and 240 min (P less than 0.001). After iv insulin, plasma glucose at 30, 40, 50, and 60 min was significantly lower than after im and sc insulin (P less than 0.001), but over the 4-h study period, the glucose-lowering effect and the area under the curves for glucose response to IRI by the three routes were the same in both lean and obese diabetic subjects. The mean basal IRI in lean patients was 18 +/- 4 microU/ml, which was significantly lower (P less than 0.05) than in obese patients (26 +/- 2 microU/ml). No significant difference was observed in fasting IRG in lean (96 +/- 12 pg/ml) vs. obese (108 +/- 10 pg/ml) patients. No significant increase in IRG was noted with equivalent amounts of sc, im, and iv injection in the lean and obese patients. These studies demonstrated that although iv injection of insulin produces a more rapid initial decline in plasma glucose, the overall glucose-lowering effect by insulin given iv, im or sc is similar in nonketotic lean or obese diabetic subjects.

Catecholamine-induced changes in plasma glucose and insulin levels in the unanesthetized rabbit.

Isoproterenol (ISO) produced dose-related increases in plasma immuno-reactive insulin (IRI) levels in unanesthetized rabbits, whereas epinephrine produced no significant changes. Dose rats of ISO or glucose that produced similar peak increases in glucose levels also produced similar increases in plasma IRI, but the responses to ISO occurred later and were of longer duration than the responses to glucose. Propranolol blocked the increase in plasma IRI produced by ISO, but the ISO-induced rise in plasma glucose was antagonized imcompletely. These data provide supporting evidence for the suggestion that the hyperglycemic activity of ISO in vivo is limited by concurrent ISO-induced changes in peripheral IRI levels.

Effect of ICI 66082, A β-adrenoceptor blocking drug on blood glucose in the rat

ICI 66082, a cardioselective β-adrenoceptor blocking agent, was found to produce hypoglycaemia in fasted rats. In fed rats a hyperglycaemic response was observed. The drug produced hypoglycaemia in fed adrenalectomised animals. The hypoglycaemic response to ICI 66082 was accompanied by elevations in plasma immunoreactive insulin (IRI) concentrations. The drug also reduced plasma glucose and increased IRI in moderately alloxan-diabetic rats. In severely diabetic animals the drug did not increase IRI concentrations and did not unequivocally lower plasma glucose concentrations. In vitro experiments showed ICI 66082 to increase glucose uptake by rat diaphragm muscle and epididymal adipose tissue. The hypoglycaemic response may be mediated by increases in plasma IRI concentrations with a possible contribution from direct effects of the drug on peripheral glucose utilization. As these responses differ from those published in relatio nto other β-adrenoceptor blocking drugs it is unlikely that the effects are due to β-adrenoceptor blockade. However, like other β-adrenoceptor blocking drugs ICI 66082 reduced isoprenaline-mediated increase in plasma IRI.

Endocrine function of the pancreas in cystic fibrosis: Evidence for an impaired glucagon and insulin response following arginine infusion

Pancreatic glucagon and insulin were determined in 10 children with cystic fibrosis (C.F.) and in a control group following stimulation by an arginine infusion. In controls the infusion of arginine induced a prompt threefold elevation in plasma pancreatic glucagon and about a sixfold increase in plasma immunoreactive insulin. In patients with C.F. the average response of both hormones was considerably less, and the base-line concentrations for glucagon were lower. The data support the hypothesis that in C.F. both alpha- and beta-cell function are affected as a result of the underlying process.

Effect of Sodium Linoleate Infusion on Plasma Free Fatty Acids, Glucose, Insulin, and Ketones in Unanesthetized Dogs

By using a continuous-flow centrifuge to separate carotid artery blood into cells and plasma, sodium linoleate was infused into the jugular vein of five conscious dogs at a mean rate of 41.9 μEq. · kg.−1 · min−1 for ninety minutes without adverse side effects. Linoleate infusion quickly elevated plasma free fatty acid (FFA) levels to approximately 1.50 μEq./ml. and was accompanied by a rapid four- to sixfold increase in plasma immunoreactive insulin (IRI) which was sustained throughout the infusion. After thirty minutes of infusion, plasma glucose began to fall, ultimately declining 35 per cent from control levels. Plasma ketone levels rose to twice their control levels during linoleate infusion but were always less than 20 per cent of the ketone levels shown to be insulinogenic in dogs. Upon termination of the infusion, plasma FFA, IRI, and ketones fell quickly to control levels, while plasma glucose rose toward normal. The half-life of plasma linoleate, estimated from the infusion rate and the increment in plasma FFA during steady-state infusion, was 0.76 minute. This result, based on net flux, validates estimates based on tracer experiments. The similarity between the metabolic responses to linoleate infusion and those previously found to oleate suggests that these effects may be common to most physiologic long-chain FFA. Stimulation of insulin secretion by high levels of FFA could thus play a role in modulating lipolytic responses and changes in glucose metabolism accompanying such responses.

Increase in plasma immunoreactive insulin following administration of insulin to the gastrointestinal tract of rabbits.

Changes in plasma insulin levels in response to enterai administration of insulin have been studied in rabbits. Insulin, when administered to the stomach, did not cause hypoglycemia at doses up to 150 U./kg. When insulin at doses over 40 U./kg. was infused to the upper jejunum via an indwelling catheter, there was a slight but significant increase in plasma insulin levels, followed by a significant fall in blood glucose. A considerable increase in plasma insulin was observed when insulin at doses over 20 U./kg. was infused to the Thiry-Velia loop of the jejunum in which no pancreatic secretion entered. With a dose of 100 U./kg., the mean plasma insulin rose promptly to the peak of 241 μU./ml., followed by a severe hypoglycemia. As judged by hypoglycemie and immunological responses, insulin can be absorbed from the intestine in a physiologically active form, but the fraction absorbed is relatively small.

Cephalic phase of insulin secretion in obese adolescents.

The influence of a visual and olfactory meal stimulus on plasma insulin, free fatty acids and glucose levels, was studied in six obese, nondiabetic young persons. There was a significant increase in plasma immunoreactive insulin with a simultaneous decrease in plasma free fatty acids without demonstrable changes in plasma glucose. The observed rise in plasma immunoreactive insulin most probably is reflex in nature. However, all levels of the nervous system including cerebral cortex, reticular formation and hypothalamus, may play different roles in the facilitation or inhibition of such reflex. The participation of one or several of the gastrointestinal hormones, such as secretin or gastrin, could explain the delayed rise in plasma insulin. Dietary habits, appetite, palatability of the offered meal and a relaxed and tranquil patient seem to be essential factors to be taken into consideration, if success is to be achieved in this type of experimental study.

Stimulation of insulin secretion by infusion of free fatty acids.

The acute elevation of plasma free fatty acid (FFA) levels by direct infusion of sodium oleate into the plasma of conscious dogs was accompanied by the rapid onset of a 2- to 12-fold increase in plasma immunoreactive insulin, and, subsequently, a marked fall in plasma glucose, even in dogs receiving intravenous glucose throughout the infusion. The magnitude of both the insulin and glucose responses correlated with the mean FFA level during infusion. A large increase in plasma insulin and fall in glucose also occurred when glycerol was infused with oleate in order to simulate endogenous lipolysis more closely. Insulin levels in pancreaticoduodenal vein blood rose markedly during oleate infusion, while plasma ketone levels rose only slightly. In contrast to the effects of oleate infusion, elevation of plasma FFA to correspondingly high levels by triolein ingestion and intravenous heparin produced only small increases in plasma insulin, which did not correlate well with the FFA level reached, and small increases in plasma glucose.The results indicate that under certain conditions elevated FFA levels may be a potent stimulus of insulin secretion. This response is modified under other conditions such as during chylomicron removal under the influence of heparin. This effect may play a role in the regulation of lipolysis and ketone formation, but determination of the exact mechanism of FFA stimulation of the pancreas and its physiological significance will require further investigation.

Plasma glucose levels in normal and adrenalectomized mice treated with streptozotocin and nicotinamide.

Serial alterations in blood glucose of normal and adrenalectomized mice following the administration of a diabetogenic dose of streptozotocin have been compared with those of similar mice pretreated with nicotinamide. An initial hyperglycemic phase, one to three hours post-injection, was observed with both streptozotocin and nicotinamide treated mice, and was drug related. In the case of streptozotocin the early elevation in blood sugar was not dependent on the presence of the adrenal gland. An initial hyperglycemic phase was recorded in fed adrenalectomized mice but was eliminated in fasted adrenalectomized mice because of decreased liver glycogen. A hypoglycemic phase at seven hours was observed with streptozotocin treatment. This was associated with a seven-fold increase in plasma immunoreactive insulin (IKI) concentration observed in streptozotocin treated normals. By twenty-four hours the streptozotocin treated mice were permanently diabetic, and had significantly depressed pancreatic insulin concentrations, while plasma insulin was still greater than control concentrations. The nicotinamide protected group demonstrated no evidence of diabetes. The mechanism of diabeto genesis of streptozotocin differs from that of alloxan.

Stimulation of insulin secretion by parasympathomimetic agents.

Effects on insulin secretion of methacholine and bethanechol given systemically and infused into the pancreatic artery were studied in the anesthetized dog. An intramuscular injection of methacholine (0.2 mg/k) resulted in a striking elevation of plasma immunoreactive insulin (IRI) in both pancreatic vein and femoral artery. A rapid intravenous injection of bethanechol (0.05 mg/k) caused a prompt and less prominent increase in pancreatic venous plasma IRI, and a somewhat delayed elevation in femoral artery plasma IRI. A constant infusion of bethanechol (1 μg/k/min) into the pancreatic artery also induced an abrupt and significant rise in pancreatic vein plasma IRI and a delayed augmentation in femoral artery plasma IRI. The increase in plasma IRI in the pancreatic and femoral vessels upon a similar local infusion of methacholine (1 μg/k/mvn) was more conspicuous than on bethanechol infusion. The elevation in plasma IRI by a local infusion of both cholinergic agents was totally blocked by a preceding infus...

Suppression of plasma immunoreactive insulin in rats given D-mannoheptulose.

SIMON and co-workers1–3 produced marked hyperglycaemia in the fasting rat with a single injection of D-mannoheptulose, a seven carbon sugar found in avocados. Their work suggests that heptulose blocks normal pancreatic secretion of insulin in response to glucose and that it induces gluconeogenesis. Coore et al.4 have demonstrated in rabbit pancreas slices that mannoheptulose blocks the glucose-stimulated release of insulin. The present investigation provides evidence that in the intact rat mannoheptulose suppresses the increase in plasma immunoreactive insulin (IRI) normally elicited by hyperglycaemia.